CN111356449B - Dutasteride solid dispersion, preparation method thereof and pharmaceutical composition containing same - Google Patents
Dutasteride solid dispersion, preparation method thereof and pharmaceutical composition containing same Download PDFInfo
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- CN111356449B CN111356449B CN201880074719.6A CN201880074719A CN111356449B CN 111356449 B CN111356449 B CN 111356449B CN 201880074719 A CN201880074719 A CN 201880074719A CN 111356449 B CN111356449 B CN 111356449B
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract
The invention relates to a dutasteride solid dispersion for improving the solubility or dissolution of a slightly soluble medicament dutasteride, a preparation method thereof and a pharmaceutical composition containing the same. More specifically, the dutasteride solid dispersion comprises a coprecipitate containing dutasteride and a water-soluble polymer carrier and an adsorbent, and is characterized in that the weight ratio of the dutasteride to the water-soluble polymer carrier contained in the coprecipitate is 1. The present invention shows equal to or higher than
The dissolution rate of the soft capsule, while exhibiting good storage stability with minimized generation of related substances.
Description
Technical Field
The present invention relates to a solid dispersion of dutasteride for improving the solubility or dissolution of a poorly soluble drug dutasteride, a preparation method thereof, and a pharmaceutical composition containing the same.
Background
Dutasteride is a compound represented by the following chemical formula I (17 β -N- [2,5-bis (trifluoromethyl) ] phenylcarbamoyl-4-aza-5 α -androst-1-en-3-one), dihydrotestosterone is a causative agent of androgenic alopecia and benign prostatic hyperplasia, and dutasteride is used for treating benign prostatic hyperplasia (benign pathological hyperplasia) and androgenic alopecia (androgenic alpecia) by inhibiting the action of 5- α reductase which converts androgen, testosterone, into dihydrotestosterone.
[ chemical formula I ]
However, dutasteride is not only a poorly soluble drug with a water solubility of only 0.038ng/mL, but also a relatively unstable drug that forms decomposition products upon oxidation and hydrolysis (Subba Rao & Radhakrishnand, chromatopoia 67,841-845 (2008)).
Thus, dutasteride is manufactured and sold in a soft capsule form, formulated in a liquid phase to improve dissolution rate, while a stabilizer is added to improve stability.
The typical product of the commercial dutasteride is the original product AVODART (A and B)
Glaxosmithkline)。
AVODART, a soluble drug which stabilizes dutasteride and can be absorbed in gastrointestinal tract upon oral administration, is a commercially available product prepared by dissolving 0.5mg of dutasteride and 0.035mg of butylated hydroxytoluene (used as a stabilizer against oxidation and hydrolysis) in 349.5mg of oily capric acid/caprylic acid monoglyceride and filling in soft capsules consisting of gelatin ((
FDA chemical review).
However, such soft capsule preparations such as avodat have problems peculiar to the soft capsule preparation.
That is, since gelatin, which is a main component of soft capsules, is sensitive to heat and moisture, not only does a problem occur that the shape changes with the softening or hardening of the capsule film during storage, or that the gelatin is crosslinked by the reaction between the contents and the film, thereby causing delay in disintegration or dissolution, but also in order to improve the stability of the characteristics of a liquid-phase preparation, it is necessary to add a stabilizer such as butylated hydroxytoluene, which reportedly may cause cancer, asthma, and behavioral disorders in infants.
Therefore, to overcome the problems such as AVODART (
) Such soft capsule dosage forms have disadvantages that formulation change studies of solid formulations containing dutasteride have been actively conducted, and several representative prior arts are described below (thus, the entire contents of the following documents are incorporated as background art of the prior arts in this specification).
Korean laid-open patent publication No. 2016-0087658 (patent document 1) discloses a pharmaceutical composition in which dutasteride is dissolved in a solubilizer, a solution of the dissolved dutasteride suspended in light anhydrous silicic acid is uniformly emulsified, and the emulsified solution is mixed with a disintegrant, a diluent, and the like, and dried. However, since this method uses a solubilizing agent in an oily liquid phase, not only a great burden is imposed on digestion and absorption, but also the amount thereof to be used in a solid preparation is as small as possible, which has a problem that the preparation of the solid preparation itself is difficult.
Korean registered patent publication No. 10-1055412 (patent document 2) discloses a process for producing a tablet, in which dutasteride, poloxamer as a surfactant, and propylene glycol monocaprylate as an oily solubilizer are all dissolved in ethanol and adsorbed onto an adsorbent composed of silicified microcrystalline cellulose and silicon dioxide. However, this method uses ethanol to improve the solubility of the main component during the processing, and may change the crystallinity of dutasteride, thereby accelerating the production of dutasteride-related substances during the preparation process and storage, and thus posing a problem of compromising stability.
Korean registered patent publication No. 10-0962447 (patent document 3) discloses a self-emulsifying composition for solubilizing dutasteride and a tablet prepared therefrom. However, the self-emulsifying emulsion composition is intended to form a spontaneously dispersed emulsion, and inevitably contains a large amount of a surfactant such as poloxamer, sucrose ester, etc., which may cause problems such as gastrointestinal disorders when taken.
[ Prior art documents ]
(patent document 1) KR 10-2016-0087658A (2016.07.22)
(patent document 2) KR 10-1055412B1 (2011.08.02)
(patent document 3) KR 10-0962447B1 (2010.06.03)
Disclosure of Invention
Accordingly, the present inventors provide a solid formulation containing dutasteride and a method for preparing the same, which do not use an organic solvent ethanol and a stabilizer harmful to the human body such as butylated hydroxytoluene, while showing dissolution and solubility equal to or higher than those of soft capsules, and having better storage stability.
The present invention has been made to solve the above-mentioned problems of the prior art,
provides a dutasteride solid dispersion which is characterized in that,
comprises the following steps: a coprecipitate containing dutasteride and a water-soluble polymer carrier; and, an adsorbent, the adsorbent being,
wherein the weight ratio of the dutasteride contained in the coprecipitate to the water-soluble polymer carrier is 1.
The present invention also provides a solid dispersion, wherein the water-soluble polymer carrier is one or more selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, a polyvinylpyrrolidone-polyvinyl acetate copolymer, a polyvinyl alcohol-polyvinylpyrrolidone copolymer, hydroxypropylmethylcellulose, and hydroxypropylcellulose.
The present invention also provides a solid dispersion, wherein the weight ratio of dutasteride to the adsorbent is 1.
In addition, the present invention provides a solid dispersion, wherein the adsorbent is one or more selected from the group consisting of aluminum magnesium silicate, silica (Colloidal silicon dioxide), attapulgite (Attapulgite), bentonite (Bentonite), and Kaolin (Kaolin).
Further, the present invention provides a solid dispersion, wherein the solid dispersion further contains a plasticizer selected from one or more of D- α -tocopheryl polyethylene glycol 1000 succinate (TPGS), polyethylene glycol 400, citric acid esters, and triacetin.
The present invention also provides a solid dispersion, wherein the solid dispersion further contains a surfactant selected from one or more of sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, transesterification products of natural vegetable oil triglycerides and polyalkylene polyols, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, propylene glycol mono-and di-fatty acid esters, pharmaceutically acceptable C1-5 alkyl or tetrahydrofurfural di-or partial ethers of mono-or polyoxyalkylene glycols, polyoxyethylene fatty acid ethers, and polyoxyethylene-polyoxypropylene copolymers.
In addition, the present invention provides a pharmaceutical composition for treating prostatic hyperplasia and androgenic alopecia, which contains the solid dispersion and dutasteride as a main active ingredient.
In addition, a preparation method of the dutasteride solid dispersion is provided, and the method sequentially comprises the following steps: heating the water-soluble polymer to a temperature higher than the melting point and stirring, and adding dutasteride into the molten water-soluble polymer;
a step of cooling the mixed solution and adding an adsorbent;
and drying the mixed solution.
The present invention also provides a method for producing a solid dispersion, which comprises the steps of adding 10 to 100 parts by weight of the water-soluble polymer to 1 part by weight of dutasteride,
the content of the adsorbent is 20-80 parts by weight relative to 1 part by weight of dutasteride.
Effects of the invention
The present invention shows equal to or higher than
The dissolution rate of the soft capsule and the generation of related substances are minimized, showing good storage stability.
Drawings
FIGS. 1 to 6 are graphs showing the comparative dissolution results of the inventive example and the control drug (AVODART).
Detailed Description
The present invention will be described in detail below.
Solid dispersions of the invention
Comprises the following steps: a coprecipitate containing dutasteride and a water-soluble polymer carrier;
and, an adsorbent, the adsorbent being,
the weight ratio of the dutasteride contained in the coprecipitate to the water-soluble polymer carrier is 1-100.
The "coprecipitate" means that dutasteride as a main active ingredient is uniformly dispersed and precipitated together with a water-soluble polymer carrier.
The solid dispersion refers to a state that the coprecipitate is adsorbed on the adsorbent, and the wettability (wettability) of the dutasteride is increased through adsorption, so that the solubility and the dissolution rate of the dutasteride are further increased.
In order to prepare an effective solid dispersion, the type and molecular weight of the water-soluble polymer carrier, the crystallinity of the drug, the solubility of the drug, the recrystallization property of the drug, the selection of the surfactant, and the composition of each constituent base material are important, and process parameters relating to the porosity, wettability, and the like of the granules also need to be appropriately adjusted. When the composition ratio of the drug is high, the drug exists in a crystalline form in the solid dispersion, and its solubility changes little or recrystallization easily occurs, so that the effect of the solid dispersion is weakened. In contrast, when the composition ratio of the polymer carrier becomes high, although the solubility and dissolution rate of the drug increase, since the route of drug administration is usually selected for oral administration, the amount of the water-soluble polymer carrier other than the drug to be used must be optimized in order to obtain a possible formulation form. In addition, since the increase in crystallinity and solubility of a drug may vary depending on the method for producing a solid dispersion, it is also important to identify a suitable method for producing a solid dispersion.
In particular, in the present invention, the weight ratio of dutasteride to the water-soluble polymer carrier contained in the coprecipitate is 1. When the content of the water-soluble polymer carrier is less than 10 parts by weight, the dutasteride and the water-soluble polymer carrier cannot form sufficient coprecipitation, and there is no effect of improving solubility or dissolution rate, which may result in failure to stabilize the dutasteride; when the content of the water-soluble polymer carrier exceeds 100 parts by weight, the formulation becomes excessively sticky and solidification becomes difficult, or the content of the solid dispersion itself becomes large, and the possibility of adjustment of excipients or the like becomes low, and there is a possibility that not only the preparation of solid preparations such as tablets or the like becomes difficult, but also the problem of aggregation and precipitation between the water-soluble polymer carriers may occur.
The water-soluble polymer carrier may be one or more of polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyvinyl alcohol-polyvinylpyrrolidone copolymer, hydroxypropyl methylcellulose, and hydroxypropyl cellulose, preferably polyethylene glycol or polyvinylpyrrolidone, and more preferably polyethylene glycol.
In particular, polyethylene glycols are classified into a plurality of kinds according to the molecular weight grades in the following table 1, and each has a different viscosity and melting point, so that those skilled in the art can consider these problems in the preparation of the coprecipitate. In particular, PEG4000 to PEG6000 are preferably used, and PEG4000 is more preferably used in consideration of physical properties such as dissolution rate, fluidity of solid preparations, and tabletting property.
[ Table 1]
The co-precipitate of dutasteride and the water-soluble polymer carrier is obtained by mixing the water-soluble polymer carrier in a molten state with dutasteride as an active ingredient. The water-soluble polymer carrier is preheated to a temperature slightly higher than the melting temperature thereof, mixed with dutasteride as an active ingredient under stirring, and brought into a liquid state. This step is completed by a cooling operation (including room temperature cooling) to become a semi-solid to solid state. If polyethylene glycol having a high molecular weight is used, heating in the presence of a plasticizer is preferred. This is because the presence of the plasticizer is preferable not only in view of lowering the melting temperature but also in view of melt uniformity.
In addition, in the present invention, when the coprecipitate is formed of only dutasteride and a water-soluble polymer carrier, a slightly viscous phenomenon occurs, making the preparation of a powdered solid dispersion slightly difficult, and thus the solid dispersion of the present invention is characterized by containing an adsorbent in order to complete a dosage form of a solid preparation. When the coprecipitate is adsorbed on the adsorbent, fluidity and tabletting property are improved, thereby having not only the advantage that the tablet is easily prepared and handled, but also, unexpectedly, the effect of increasing dissolution rate. In general, since an adsorbent has a property of releasing bound contents to a certain extent depending on the concentration, it is abnormal that the elution of the coprecipitate is increased by using the adsorbent. It is presumed that this is probably due to the fact that the interaction between the coprecipitates is reduced by the presence of the adsorbent, but further studies are required for this clear mechanism.
The adsorbent may be selected from one or more of magnesium aluminium silicate (including magnesium aluminium metasilicate), silicon dioxide (including colloidal silicon dioxide), attapulgite, microcrystalline cellulose, lactose, bentonite (Bentonite), and Kaolin (Kaolin), and may preferably be magnesium aluminium metasilicate.
Preferably, the adsorbent is contained in an amount of 20 to 80 parts by weight relative to 1 part by weight of dutasteride. When the amount is less than 20 parts by weight, the binding effect of the adsorbent to the polymer carrier is not significant, and the effect of improving the flowability, tabletting property and dissolution property may be insufficient; when the amount exceeds 80 parts by weight, the size of the tablet is excessively increased, and the physical properties such as dissolution property may be adversely affected.
The present invention may further comprise a plasticizer. Any substance that can facilitate melt molding of the water-soluble polymer carrier may be used, and preferably, one or more of D- α -tocopheryl polyethylene glycol 1000 succinate (TPGS), polyethylene glycol 400, citrate, and triacetin, and preferably, polyethylene glycol 400 may be used. Preferably, the plasticizer is used in an amount of 1 to 10% by weight relative to the weight of the solid dispersion as a whole.
The solid dispersion can be prepared by a preparation method of the dutasteride solid dispersion, which comprises the following steps: adding dutasteride in a molten state of the water-soluble polymer which is heated and stirred to be molten; a step of cooling the mixed solution and adding an adsorbent; and drying the mixed solution. In a preferred embodiment, the water-soluble polymer may be contained in an amount of 10 to 100 parts by weight and the adsorbent may be contained in an amount of 20 to 80 parts by weight, based on 1 part by weight of dutasteride.
The solid dispersion prepared according to the present invention may be used as it is as a pharmaceutical agent for oral administration, or the solid dispersion prepared in the present invention may be added with pharmaceutically acceptable excipients, disintegrants, binders, colorants, stabilizers, sweeteners, lubricants, etc., and may be prepared into powders, granules, capsules, tablets, etc., preferably, film-coated tablets in which a tablet form is coated.
The present invention also provides a pharmaceutical composition for treating prostatic hyperplasia or androgenic alopecia, which contains the solid dispersion as an effective ingredient.
The pharmaceutical composition according to the present invention may contain the above solid dispersion alone or may be formulated in an appropriate form together with a pharmaceutically acceptable carrier, and may further contain an excipient or diluent. The term "pharmaceutically acceptable" refers to non-toxic compositions that are physiologically acceptable and do not generally cause allergic reactions such as gastrointestinal disorders, vertigo, or the like when administered to humans.
The pharmaceutical composition of the present invention may further comprise a surfactant selected from one or more of sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, transesterification products of natural vegetable oil triglycerides and polyalkylene polyols, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, propylene glycol mono-and di-fatty acid esters, pharmaceutically acceptable C1-5 alkyl or tetrahydrofurfuryl di-or partial ethers of mono-or polyoxyalkanediols, polyoxyethylene fatty acid ethers, and polyoxyethylene-polyoxypropylene copolymers. Although the surfactant is advantageous in terms of improving the dissolution and solubility characteristics of poorly soluble dutasteride, when the content thereof is excessive, gastrointestinal disorders and the like are caused, and it is desirable not to overdose. Unlike the prior art, in the present invention, since the dissolution and solubility of the solid dispersion are ensured, the surfactant added does not have to be excessive. In view of this, the surfactant to be further added is preferably 20% by weight or less, more preferably 15% by weight or less, and still more preferably 10% by weight or less, based on the total weight of the composition.
The pharmaceutically acceptable carrier may further comprise, for example, a carrier for oral administration or a carrier for parenteral administration.
Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
The pharmaceutical composition of the present invention may contain, in addition to the ingredients, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents and the like. Other pharmaceutically acceptable carriers and formulations can be found in the literature (Remington's Pharmaceutical Sciences,19th ed, mack Publishing company, easton, PA, 1995).
The composition of the present invention can be administered to mammals typified by humans through various routes. For example, it can be administered orally or parenterally. The parenteral administration may be intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or intrarectal, but is not limited thereto.
The pharmaceutical composition of the present invention may be formulated into preparations for oral administration or parenteral administration according to the administration routes as described above.
In the case of a preparation for oral administration, the composition of the present invention may be formulated into powder, granules, tablets, pills, sugar-coated tablets, capsules, liquids, gels, syrups, slurries, suspensions and the like by a method known in the art. For example, the preparation for oral administration may be prepared by mixing the active ingredient with a solid excipient, pulverizing the mixture, adding an appropriate adjuvant, and processing the mixture into a granule mixture to obtain a tablet or a sugar-coated tablet. Suitable excipients may include, for example: sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, and the like; starches, including corn starch, wheat starch, rice starch, potato starch, and the like; celluloses including cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and the like; and fillers including gelatin and polyvinylpyrrolidone, and the like. In addition, as a disintegrating agent, crosslinked polyvinylpyrrolidone, agar, alginic acid, sodium alginate, or the like may be added as necessary.
In addition, the pharmaceutical composition of the present invention may further contain an anticoagulant, a lubricant, a wetting agent, a perfume, an emulsifier, a preservative, and the like.
In the case of a preparation for parenteral administration, the composition of the present invention can be formulated into injections, creams, lotions, ointments for external use, oils, moisturizers, gels, aerosols and nasal inhalants by methods well known in the art. These formulations are described in the literature of prescriptions known in the Pharmaceutical chemistry field (Remington's Pharmaceutical Science,19th ed., mack Publishing Company, easton, PA, 1995).
Hereinafter, the present invention will be described in more detail by referring to examples. It is to be understood, however, that the following examples are illustrative only of the present invention and are not intended to limit the scope of the claims.
Examples
Film-coated tablets were prepared by the following basic method, and were formulated in the proportions shown in the following tables 2 and 3.
Preparation method
Melting the water-soluble polymer carrier and the plasticizer at 70-80 ℃, stirring and adding dutasteride to obtain homogeneous suspension. The suspension is cooled at room temperature, stirred, and added with an adsorbent to obtain a homogeneous solid dispersion (the solid dispersion may be subjected to a process such as drying or powdering, if necessary). After adding an excipient, a disintegrant, and a surfactant to the solid dispersion and homogeneously mixing, a lubricant is further added and post-mixing is performed. The post-mix was compressed and prepared into uncoated tablets.
[ Table 2]
[ Table 3]
Example 13
Opadry blue (03F 40519) was coated on the uncoated tablet of example 10 with 5.58mg of purified water and 22.32mg of ethanol as solvents to prepare a film-coated tablet.
Evaluation of formulation Properties
Hardness was measured by a hardness tester (hardness tester, international engineering KTF-25), and brittleness was measured by a brittleness machine (KIYA SEISAKUSHO 3880).
When the formulation was evaluated, the tableting property was judged to be good when the brittleness was 0.5% or less, the angle of repose of fluidity was 45 degrees or less, and the CI value was 30% or less.
Evaluation of elution Property
[ dissolution test conditions ]
Use of
Soft capsules were used as a control using the dissolution test conditions under standard and test methods (0.1N HCl,2.0% SLS conditions). EXAMPLES Using dissolution under control drug standards and test methodsTest conditions, or conditions for adjusting 0.3% SLS of pharmaceutical equivalence test conditions were used.
The results of the preparation properties of the examples are summarized in Table 4, and the dissolution results are shown in FIGS. 1 to 6.
[ Table 4]
The hardness of examples 1 to 8 was measured to be 2 to 4kP, and the hardness was slightly inappropriate when coating was performed, and when colloidal silica (syloid) was used, the flowability was poor when tabletting was performed due to the influence of the bulky property, and the mass deviation was 10% or more.
In contrast, examples 9 and 10 were good in fluidity and had a hardness of 5 to 7kP, and no problem occurred in coating.
Examples 11 and 12 are problems that a kneading process is problematic or a screen is not passed after mixing, resulting in a problem that tabletting is impossible.
Examples 1 to 10 were substantially good in dissolution, and example 3 had a final dissolution rate of 70% and was initially lower than the control drug. In contrast, in example 13, as shown in fig. 6, the dissolution of 80% or more was shown after 45 minutes based on the control test method, and the dissolution characteristics were shown to be superior to those of the control as a whole.
Evaluation of storage stability
The storage stability was evaluated based on the relevant substance test standards, and as shown in table 5 below, it was judged that there was no problem in storage stability.
[ Table 5]
Claims (5)
1. A solid dispersion, comprising: the composition contains a coprecipitate of dutasteride and a water-soluble polymer carrier, an adsorbent and a surfactant;
the water-soluble polymer carrier is polyethylene glycol 4000-6000;
the weight ratio of the dutasteride to the water-soluble polymer carrier in the coprecipitate is 1 to 10-100;
the surfactant is contained in an amount of 20 wt% or less with respect to the total weight of the solid dispersion;
the adsorbent is magnesium aluminum silicate, and the content of the adsorbent is 20-80 parts by weight relative to 1 part by weight of the dutasteride.
2. The solid dispersion of claim 1, further comprising a plasticizer selected from one or more of D-alpha-tocopheryl polyethylene glycol 1000 succinate, polyethylene glycol 400, citrate, and triacetin.
3. The solid dispersion according to claim 1, wherein the surfactant is selected from one or more of sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, transesterification products of natural vegetable oil triglycerides and polyalkylene polyols, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, propylene glycol mono-and di-fatty acid esters, pharmaceutically acceptable C1-5 alkyl or tetrahydrofurfural di-or partial ethers of low molecular weight mono-or polyoxyalkanediols, polyoxyethylene fatty acid ethers, and polyoxyethylene-polyoxypropylene copolymers.
4. A pharmaceutical composition comprising the solid dispersion of claim 1 and containing dutasteride as a main active ingredient, for treating prostatic hyperplasia and androgenic alopecia.
5. A preparation method of a dutasteride solid dispersion is characterized by sequentially comprising the following steps:
heating the water-soluble polymer carrier to a temperature higher than the melting point and stirring, and adding dutasteride into the molten water-soluble polymer carrier to obtain a mixed solution;
a step of cooling the mixed solution and adding an adsorbent;
drying the mixed solution; and
a further step of adding a surfactant,
wherein the water-soluble polymer carrier is polyethylene glycol 4000 to 6000;
the content of the water-soluble polymer carrier is 10 to 100 parts by weight relative to 1 part by weight of dutasteride;
the surfactant is contained in an amount of 20 wt% or less with respect to the total weight of the solid dispersion;
the content of the adsorbent is 20 to 80 parts by weight relative to 1 part by weight of dutasteride.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2017-0155985 | 2017-11-21 | ||
| KR1020170155985A KR101897995B1 (en) | 2017-11-21 | 2017-11-21 | Solid dispersion comprising dutasteride, method of preparation thereof, and pharmaceutical composition comprising the same |
| PCT/KR2018/013684 WO2019103373A2 (en) | 2017-11-21 | 2018-11-12 | Solid dispersion of dutasteride, method for producing same, and pharmaceutical composition comprising same |
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| Publication Number | Publication Date |
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| CN111356449A CN111356449A (en) | 2020-06-30 |
| CN111356449B true CN111356449B (en) | 2022-12-02 |
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|---|---|
| US (1) | US11324760B2 (en) |
| JP (1) | JP6966644B2 (en) |
| KR (1) | KR101897995B1 (en) |
| CN (1) | CN111356449B (en) |
| WO (1) | WO2019103373A2 (en) |
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|---|---|---|---|---|
| KR101897995B1 (en) | 2017-11-21 | 2018-09-12 | 한국프라임제약주식회사 | Solid dispersion comprising dutasteride, method of preparation thereof, and pharmaceutical composition comprising the same |
| WO2020066392A1 (en) * | 2018-09-25 | 2020-04-02 | 日新製薬株式会社 | Orally administered solid preparation and production method therefor |
| WO2022065618A1 (en) | 2020-09-28 | 2022-03-31 | 주식회사 위바이오트리 | Metal (hydr)oxide composite comprising poorly soluble drug, method for manufacturing same, and pharmaceutical composition comprising same |
| KR102378590B1 (en) | 2020-09-28 | 2022-03-24 | (주)위바이오트리 | A metal hydroxide/oxide complex comprising poorly water soluble drug, a method for preparing the same, and a pharmaceutical composition comprising the same |
| CN113750051B (en) * | 2021-10-20 | 2023-05-23 | 沈阳药科大学 | Solid andrographolide solution for oral administration and preparation method thereof |
| WO2024019439A1 (en) * | 2022-07-19 | 2024-01-25 | (주)인벤티지랩 | Sustained-release injectable composition containing dutasteride |
| US20240165108A1 (en) * | 2022-08-09 | 2024-05-23 | Glaxosmithkline Intellectual Property Development Limited | Novel use |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060204588A1 (en) * | 2005-03-10 | 2006-09-14 | Elan Pharma International Limited | Formulations of a nanoparticulate finasteride, dutasteride or tamsulosin hydrochloride, and mixtures thereof |
| US20080311162A1 (en) * | 2007-05-16 | 2008-12-18 | Olivia Darmuzey | Solid form |
| KR100962447B1 (en) | 2010-02-24 | 2010-06-14 | (주)비씨월드제약 | Composition for self-emulsifying of insoluble dutasteride and the tablet containing thereof |
| KR101055412B1 (en) | 2010-11-19 | 2011-08-08 | (주)비씨월드제약 | Composition for self-emulsifying preparation comprising dutasteride and manufacturing process thereof |
| EP2468262A1 (en) * | 2010-12-06 | 2012-06-27 | Krka Tovarna Zdravil, D.D., Novo Mesto | Pharmaceutical composition comprising dutasteride |
| KR102382963B1 (en) * | 2015-01-14 | 2022-04-05 | 동아에스티 주식회사 | Dutasteride composition in tablet form with improved stability |
| KR101561406B1 (en) * | 2015-02-02 | 2015-10-16 | 환인제약 주식회사 | Solid dispersion containing dutasteride and composition containing the solid dispersion |
| KR101897995B1 (en) * | 2017-11-21 | 2018-09-12 | 한국프라임제약주식회사 | Solid dispersion comprising dutasteride, method of preparation thereof, and pharmaceutical composition comprising the same |
-
2017
- 2017-11-21 KR KR1020170155985A patent/KR101897995B1/en active IP Right Grant
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2018
- 2018-11-12 US US16/761,990 patent/US11324760B2/en active Active
- 2018-11-12 JP JP2020526281A patent/JP6966644B2/en active Active
- 2018-11-12 CN CN201880074719.6A patent/CN111356449B/en active Active
- 2018-11-12 WO PCT/KR2018/013684 patent/WO2019103373A2/en active Application Filing
Also Published As
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|---|---|
| US20200306266A1 (en) | 2020-10-01 |
| KR101897995B1 (en) | 2018-09-12 |
| WO2019103373A3 (en) | 2019-07-18 |
| US11324760B2 (en) | 2022-05-10 |
| JP6966644B2 (en) | 2021-11-17 |
| CN111356449A (en) | 2020-06-30 |
| JP2021501195A (en) | 2021-01-14 |
| WO2019103373A2 (en) | 2019-05-31 |
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